Dr. Anthony Fauci has led research on AIDS since the early 1980s. As the director of the National Institute of Allergy and Infectious Diseases (NIAID), he pioneered AIDS treatment protocols and he has become a highly respected adviser to the federal government on AIDS. Here, he recounts how visiting patients in Uganda, who weren't getting access to expensive antiretroviral drugs, triggered in him "an absolute resolve that this is just something that as human beings we can't accept." Fauci went on to help shape President George W. Bush's Emergency Plan for AIDS Relief (PEPFAR), which will distribute $15 billion to 15 countries over five years for treatment and prevention. He also talks about his complicated relationship with gay activists over the years; from being booed while advocating safe sex to developing relationships with gay activists during the 1990s that "transformed" the drug approval process. This is an edited transcript of three interviews conducted on Jan. 28, March 10, and June 5, 2005.

Well, my first experience with HIV/AIDS I remember very clearly. I was sitting in my office at the NIH [National Institutes of Health] Clinical Center going through some literature that comes on my desk daily, and I saw the first Morbidity and Mortality Weekly Report [MMWR]from the CDC [Centers for Disease Control and Prevention] about these unusual cases that had occurred in L.A. and New York -- Pneumocystis pneumonia and Kaposi's sarcoma.

I remember being somewhat puzzled as to what exactly this meant. Was it some strange drug that a group of gay men had consumed that acutely and severely immunosuppressed them for them to get Pneumocystis and Kaposi's sarcoma, which we had known for years and years had been associated with an immunosuppressed state? I remember getting a feeling of anxiety about that, of this unknown, but it was only a few cases, and I had a lot of other things going on, so I pushed it to the back of my mind. But it kind of stood there for a while.

Then when the second MMWR came out later in the summer, then I remember getting a very chilly feeling that we were dealing with a brand-new communicable disease. I had no idea what it was, but the way it was acting was strongly suggestive of it being a communicable disease. It was an interesting, unique feeling, because it isn't very often in one's career that you run into truly a new disease. So I felt first something a little vague, a little confusing, and then a feeling of some significant anxiety about what the heck was going on here.

What was it that gave you that anxious feeling?

The anxious feeling was the seriousness of it. These people got very, very sick. We did not know at the time that we were looking very likely at someone who had been infected years before and we were seeing the advanced stage of disease. Retrospectively everything fits into place. All the pieces of the puzzle are there, but back then we had no idea whether someone got exposed to whatever this agent was and within two weeks or three weeks got acutely ill and died or got acutely ill and had major immunosuppression. That was a big unknown.

As it evolved over the months and the years, the landscape started to become clearer and clearer, and this mosaic of puzzles started to come together. Very soon after the second Morbidity [and] Mortality Weekly Report, when we started to hear now of cases from New York and Washington and San Francisco, it clearly was not something that was just isolated to the West Coast and to New York City. It became clear it was an immunosuppressive disease. For some of us who were paying attention to it, it was also clear that it was an infection of some sort. We had no idea what it was, but it was likely communicable and, given the epidemiological circumstances, likely sexually transmitted and perhaps blood-borne transmission, which became even more clear as the first injection drug user cases came in.

At that point I made a decision, and I tell you, reflecting back now on that, I'm not sure why, but I was caught up in the uniqueness of it and the opportunity to pursue this mystery. Being both an infectious disease person and an immunologist, ... I was seeing both of my subspecialty areas of expertise converging on this as-yet-unknown disease. So I made a decision that although we were quite successful in our studies in immunology and fundamental basic immunology and immune-mediated diseases, that I would convert my laboratory to trying to get some of these patients at the NIH and study them to try and figure out just what was going on.

It was that fall, late fall of 1981, that we began getting referrals of patients with this evolving disease, and from that time on we've been intensively studying HIV. It went from studying people in which there was a complete mystery to the major breakthrough when the virus was isolated, when we at least knew what we were dealing with, and then you could have a much more strategic approach to studying disease when you had the virus in hand and you knew what the virus did. And that was an exploding field at the time. ...

... What was the significance of [the 2000 International AIDS Conference in] Durban, [South Africa]?

…To challenge the assumption that just because … drugs cost a lot of money and require daily administration, that you would rule out the possibility that people in developing nations, particularly in sub-Saharan Africa, would ever have access to those drugs.

This was challenged in Durban. The main phrase that you heard was "Why not?" Tell me why we can't do this, because the easy excuse was that the drugs are just too expensive. It's $18,000, $20,000 a year for a regimen. Forget it. The health care per capita costs that are designated to people there was $60, $70, $80 at the most, sometimes $1 or $2, sometimes measured in cents, as opposed to in our country, where it's thousands of dollars. So there was no way that anybody was going to get drugs.

Then all of a sudden the prices of the drugs dropped. Then there were generics. Then there were companies that were giving it away. So the next thing was, well, you don't have an infrastructure. How are you going to get the drugs to them? So then when we started to look and went to Africa several times, [we] said, … why can't we get out into the bush, get to the people, get them tested, and get them on medications? ...

...When I went to Uganda in the '90s and went into a hospital in Kampala and immediately related to my medical colleagues -- these were African physicians and nurses who were well trained, who understood the disease, and I made rounds with them on patients. ... What we saw was something that you don't almost ever experience in the United States: making rounds with someone who you know what's wrong with them, absolutely, and you have nothing to do for them. ...

You know sometimes you go and make rounds on a patient, they have a very advanced cancer and you've tried all the chemotherapies and there's nothing left, but here's something where a simple drug could have a major impact either on their opportunistic infection -- cryptococcus, tuberculosis or what have you -- or HIV/AIDS with an antiretroviral drug and you just have nothing to offer then but just general care. And you go bed after bed after bed. That was really for me the defining and crystallising event that what I had known from a broad conceptual and philosophical standpoint from what we had been doing in Zaire and in Haiti and in other places, to actually be there and make rounds on patients in which you can't do anything.

That triggered in me this absolute resolve that this is just something that as human beings we can't accept. You're looking at it straight in the eye and you say, "What am I going to do?" So we went back home, and that's when we started agitating for overcoming these artificial barriers and reasons that you can't even try to do anything in a developing nation because of the lack of infrastructure, the lack of ability to get drugs there, the lack of people to understand the complexity of the situation.

In fact, all of those proved to be difficulties, but not insurmountable obstacles. That was really crystallized by the expression of the activist movement that we saw in the global meeting in South Africa, ... and it was that impetus that led to the resolve to get treatment, care and prevention into the trenches in developing nations in whatever manner or form we can.

... Right after Durban, the Global Fund was announced. How did you start getting involved with that?

In the Infectious Diseases Institute here at NIH, we felt that we needed to change our own paradigm and do some studies in countries in sub-Saharan Africa to figure out how we can best get to them the kinds of advances that were being made in the Western world. …

In 2002 the president asked [Department of Health and Human Services] Secretary [Tommy] Thompson and myself and a couple of others to go to Africa, take a look and report directly back to him about what can the United States do. This was before any drugs were available. But what was available was the demonstration that a very inexpensive, cheap, single dose of a drug like nevirapine given to a mother and to the baby immediately after birth in a single dose could block by a significant amount the transmission from mother to child.

We went to Africa in the spring of '02, Secretary Thompson and I and members of his staff. Secretary Thompson was very impressed with what he saw and felt that one thing we could do right away was to have an impact on mother-to-child transmission. When we got back, we reported to the president through him. ... We put together a program proposal of $500 million for the prevention of mother-to-child transmission for acceptance or not by the president.

Why was he interested?

He has a genuine interest in how the United States of America can help less fortunate countries and less fortunate people, and health is one of the issues that he felt very strongly about, and that's why he sent us. We came back, and he said, "Give me a plan," so we put together a $500 million program. He reviewed it. We had a formal presentation to him in the White House with all of his senior staff there. He accepted it on the spot. ... He said, "Done, let's do it."

Then when the meeting was over, literally within minutes, he grabbed one of his very senior staff people, Josh Bolten, who at the time was the deputy chief of staff, and told Josh in front of me that: "This is terrific, but we have got to do more. We have got to do something on a much grander scale. There is a lot more that we can do. Think about it. Work on it. Put together a plan, and then get back to me." At that point, I got very heavily involved with many people on the White House staff. ... It was my job to essentially map out what a program of prevention, care and treatment would be in the same general area of the sub-Saharan African and Caribbean countries that we initiated the $500 million program. We went on an intense massaging back and forth different versions, the real Mercedes version, the Chevrolet version, the intermediate version.

What do you mean?

What happens if we do everything we could possibly do with a lot of money? What happens if we do a moderate amount because we wouldn't be able to free up enough money from Congress? What happens if we do a minimum amount? What is the bang for the buck? Obviously the biggest bang for the buck was to really go at it big time, and that was a $15 billion program.

We put together a program, and we worked on it intensively from the summer of '02 right through the fall into the winter in December of '02 until -- you know, there were days when you thought it was on and days you thought it was off, but there was always that interest, always the White House staff coming back: "Give us a little version of this"; "Explain this"; "Why did you do this?," etc., etc. It was obviously reflecting a very, very keen interest.

Then, right at the end of December, the beginning of January, when they were getting ready for the State of the Union address, another burst of interest came up, and they were trying to think of things, and the president was thinking of things he could do to have an impact. We went down, and we made a presentation. In fact, we brought some Africans and some Haitians in to put a real face on the kinds of things that we'd be able to do. I was on pins and needles because I wasn't sure what version the president was going to want.

Why did you bring in Africans to help make the proposal?

Well, what happened is that the White House staff said: "We believe you, Tony, but you're a white American who works for the federal government. We want to hear is this thing feasible from people who are in the trenches, so you bring to me people who are actually doing those things." I brought to the White House ... Peter Mugyenyi from Uganda, who was pioneering his work in Uganda; Bill Pape, who is the leader in Haiti who was doing the Haitian program; Eric Goosby, who was working in Rwanda for an American foundation; and Paul Farmer of Harvard University, who spends a lot of time in Haiti. Those were four people who really were doing it and were in the trenches themselves. We brought them here to confirm that this is doable; this isn't pie in the sky. If you get the resources, it will happen. ...

Who did you make the presentation to?

Ultimately we made it to OMB [Office of Management and Budget]. We made it to the Treasury. We made it to literally everybody, and then the president's staff, probably Josh Bolten himself and [then-Chief of Staff] Andy Card and others and certainly Secretary [Colin] Powell was involved from the State Department and some of the congressional leaders, Sen. [Bill] Frist [R-Tenn.] and others. The White House staff made the presentation to the president, and then I remember getting a call right a day or so before the State of the Union address, saying: "Cancel everything you're doing. Come down to the White House. We're going to go with it, and we want to put together the correct language, so we will work on what he is going to say." I just went down there, and we worked for hours and hours, and then he came out with his announcement in January of '03 in his State of the Union address, and now the program is viable, up and running.

But the critical issue that people don't appreciate or understand is that it was driven by the president. … He said he wanted it to be feasible; he wanted it to be bold, and he wanted it to be accountable. … And that's exactly what it turned out to be.

What does PEPFAR mean to you personally?

Well, we had put in essentially two-thirds of a year of working on this model, and I was obviously hoping that we would go with the real full-blown version of it and not fewer countries and less money. So when I say on pins and needles, I wasn't sure if it was going to be accepted, and if it was, I wasn't sure whether the bold plan would be accepted. So knowing something was going to happen ... [the White House staff will] never tell you specifically what's going to happen until it's ready to happen, but you could read between the lines that something good was going to happen. But I wasn't sure how good it was going to be. Then when I heard the news that it was the whole shooting match, that was absolutely wonderful. I mean, to me that's a historic decision.

Can you explain how the body's immune system works and how AIDS disrupts it?

Well, the body's immune system is like any other system of the body. Each of them have their vital function for the human host. … The immune system's goal is to protect the body against invaders either from without, such as microbes, or from within, such as cancers and different types of neoplastic transformation.

It has a number of components to it. It has a nonspecific component, which we call the innate immune system, where it recognizes something that it didn't necessarily see before and gives the first-line approach to attack whatever it is -- a bacteria, a virus, a parasite.

Then, over the evolution of the species, we have what's called the adaptive immune system, which has a series of cells which are capable of recognizing microbes and other antigens by a whole series of complex receptors that when they do recognize, they trigger a series of events. They could secrete proteins; they could actually migrate to a site of inflammation or infection; they can kill cells that are infected or cells that have been transformed, and they do this by a series of capabilities that have evolved over the evolution of mankind, where you can essentially recognize any given determinant that you will ever come in contact with.

What the immune system of man has in its advanced development is what we call immunological memory, so that once it sees something for the first time, when it sees it the second or the third time, it can respond against it in a way that's much more accelerated than when it sees it for the first time….

What about HIV?

Interestingly, the way many, many, if not all, viruses work is they co-opt parts of the body that are essential for the body's function. A virus will bind to or get into a cell by a receptor that wasn't made for that virus; it was made for some other very normal and necessary function. Most viruses do that, and when they get into the cell, they use the cell's machinery to propagate itself. It just so happens that the major receptor for HIV is a molecule … that's the critical molecule on one of the most critical cells in the immune system….

Years and years ago, at the beginning of the AIDS epidemic, when I was trying to explain to the lay public about the central and focal role of the CD4 positive T-cell, I drew a schematic cartoon in which the immune system, with all its complexity, is like a very complicated symphony orchestra, and the conductor of that symphony is the CD4 cell. It has the capability of secreting molecules that allow cells to talk to each other; it's the central focal conductor of the symphony of the immune system. If there was one cell that if a virus was to pick that cell, if it was going to attack that cell, it would do the most damage to the immune system, CD4 positive cells would be a very good bet. That's exactly what the virus has done. ...

[After the virus comes along and disrupts the orchestra, how does the body become susceptible to disease?]

... Without that CD4 cell, your defenses are severely compromised, so what happens is that over time, as the CD4 cell numbers and function continue to diminish, the body's normal capability of dealing with infections that would otherwise not be a problem for a healthy person, all of a sudden that person becomes highly susceptible, which is the reason why you call them opportunistic infections. They seize the opportunity of a weakened immune system to infect the body and to cause disease under circumstances which they would not have a chance to do that. That's the reason why, if you look at the names of these infections, they're not common infections that a normal person in everyday life would get, things like Pneumocystis carinii pneumonia and cytomegalovirus [CMV] and Mycobacterium avium-intracellulare [MAI] and a variety of others. They also get common infections like tuberculosis, but for the most part they get these infections that would not otherwise be a problem for a person….

So when the virus was a mystery, all you could see were these opportunistic infections that physicians around the world were noticing. Can you tell us about that period?

Well, it was a period of evolving mystery, where more and more facts came about, and what was waiting to happen to tie it all together was the discovery of the virus. We were seeing things that were strongly suggestive that we were dealing with a communicable disease, very likely a virus. You couldn't see it. You look in the cells; you couldn't grow it, at least initially, and most everybody thought it was a virus. We saw the evolving epidemiology, which again gave stronger and stronger evidence that you were dealing with something that was spread through blood or blood products and that was spread through sexual contact….

We thought it was just a disease -- naively so…. It looked like a disease of gay men. It was not. It was a disease of sexual transmission, and it just so happened that [it appeared] at the time of the evolving of the permissiveness of sexuality among the gay community, back in that period of time after they had just essentially been able to win their freedom to express themselves sexually. Unfortunately it came at a time when the bathhouse culture was a perfect breeding ground for a sexually transmitted disease.

You saw it sexually in gay men. You saw it in injection drug users. Then you started to see indications in even the sexual partners, for example, of injection drug users. Then we saw it in people with blood transfusions. We saw it in hemophiliacs, and we even started to see it in children born of infected mothers. This mosaic of information was unfolding before us, and it was very clear that we were dealing with a communicable disease that was spread by these various modalities.

The real obvious breakthrough that everyone admits is that when the virus was discovered and a test to determine infection before you became sick, the serological test … indicated that the problem was much more extensive than you would have thought, because as we described back in the '80s, it was like an iceberg, and what we were seeing was the tip of the iceberg, people who had already become clinically ill, where they came to a physician because they were sick. But beneath that, beneath the surface were the many, many people who were infected. They didn't know they were infected and were not yet ill. The first cohorts of patients that we admitted to the Clinical Center at the NIH in 1981, '82, '83 and then in '84, before we knew that there was this enormous number of people who were infected and had not yet gotten sick, every person we saw had advanced disease, so we had a skewed appreciation of what this disease was all about, because we thought that you get HIV infected and you were deathly ill and that was it, not fully realizing the vast numbers of people who were incubating this illness for years and years.

[How was the virus discovered?]

It evolved because there was a lot of talk and activity that this was a retrovirus, ... since retroviruses, [such as] HTLV1, which had been discovered a few years earlier, were responsible for a certain type of a T-cell lymphoma and leukemia, maybe this was a form of HTLV1. When [virologist Dr. Robert] Gallo was first pursuing it, he actually called it HTLV3, but it turned out it wasn't an HTLV at all. It was a different type of a retrovirus. But people were searching for it.

There was some isolation, electromicroscopic identification, of a viral particle by the group in France with [virologist] Luc Montagnier, but not yet the direct link of causality. Then the following year, in 1984, when Gallo and Montagnier both were pursuing this and Gallo showed that there really clearly was this link. So the combination of the initial identification without the definitive proof by Montagnier and then the definitive proof with the Gallo lab, and then with Montagnier -- [there was] the very, very well-known dispute that went on back then about who was the person who really discovered it, and now everyone agrees that there was co-discovery of it. …

And then right after that was the development of the blood test?

Well, once the virus was isolated, it was one of the most exciting and accelerated eras of discovery that you could possibly imagine, because once you got that virus, then all the molecular virologists came in and started sequencing and describing the various genes, structural genes, regulatory genes. The antibody test was discovered right after the discovery of the virus, literally within months, and then it came out in 1985. We started screening the blood in the United States and other developed nations in 1985. ... Then we could get a feel for what the extent of this infection was, not only in the United States and other developed nations, but also beginning in developing countries.

We first started to get the inkling of the fact that the problem was probably more extensive, as we now know it is in developing nations. Then, not even a year later, we began screening various compounds for activity against HIV, and that's how the first effective drug against HIV was discovered, by screening off-the-shelf compounds such as AZT, or zidovudine. ...

The first clinical trial of AZT versus a placebo in patients who were HIV infected showed very, very clearly that, at least in the short run, AZT was of great benefit. So then you had AZT, and then after that you had ... the next class, which was the protease inhibitors, and then things began to be used in combination. If you look at how things took off -- understanding the virus, screening the population, screening the blood, screening for drugs -- it was an extraordinary period from 1985 until the mid-90s.

... [But AZT didn't turn out to be a simple answer. Could you tell us about that?]

It was an important event, because everyone in their heart of hearts were hoping that AZT would be the answer. The whole issue of the HIV epidemic is such an enormous play with many acts. But now that we're well into the play, we know that AZT alone was just not going to work, first of all, because we know the virus has an extraordinary capability of developing resistance. If you use a single drug it's inevitable. You give a single drug of anything, you're going to wind up resistant. That's the reason why we now have the combination therapies that are quite successful.

What happened is that in the United States, when we did this study on AZT, we saw that curve where the people who got AZT did well, but the duration of it was not particularly comforting, because it lasted a very short time…. That was the wake-up call, that although AZT was an important advance, it was only the first of many necessary steps.

Why did the introduction of protease inhibitors and triple cocktails help?

HIV isn't too different than some other microbes, such as tuberculosis, which really requires, because it is so prone to develop resistance, more than one drug. ... So we had one target, reverse transcriptase. There were two types of drugs, the nucleoside reverse transcriptase inhibitors [NRTIs], like AZT, and the non-nucleoside reverse transcriptase inhibitors [NNRTIs]… What we were seeing was an evolution of first one drug, then two drugs that almost made it but not quite. It just did better than one, but not quite because they were essentially going for the same target. …

Then when the protease inhibitors came, [they] were looking at another target, the protease enzyme, so putting those two things together in a triple combination or more was the first example of seeing the viral load go down to below detectable level and to stay there in many patients for a considerable period of time.

We also learned that if you were experienced with HIV drugs before, the likelihood of your responding to the triple combination was less than if you were a fresh patient who had never seen the drug. The reason is if you've seen the drug before, you likely had already developed resistance to one or more of the components of the combination, so although the combination would likely work in you, it wouldn't work as robustly if you started never having received the drug….

How does the virus develop drug resistance?

Well, if you look at the virus as a species, what it has is two capabilities that allow it to survive: It replicates rapidly, and it mutates. Just the way the human species adapts to things by our intellect, by how our bodies get stronger with better nutrition, that takes years and decades to evolve. Not so with a virus. The virus does it in minutes to days. …

By continually replicating and continually mutating, it will always be trying to figure out a way to get around what you, the human species, your body, your drugs drop in front of the virus to get in its way. The best way to prevent it from responding is to totally suppress its replication, because when you do that, it can't replicate, and if it can't replicate, it can't mutate.

Now, the problem is that -- and this is one of the sobering things that we're facing now about HIV -- that even under the best of circumstances, when you've suppressed the virus to below detectable level, if you go deep into the cells and look at the cells and look at the lymph nodes, you still see some residual evidence of replication. Even under the best of circumstances, you haven't completely suppressed that. There's always that little lingering capability of escaping from the drug-induced control. ...

… [What were the misimpressions about HIV, even in the mid-'90s?]

The misimpressions were that if you begin to treat people in a very aggressive way that you are going to truly eradicate the virus…. There was this feeling that really during a considerable period of time in the evolution of disease in a person that somebody really had no particular activity of the virus. That became something that was proven incorrect over a period of years. …

As we got to '93, '94 or '95, it became very clear that even early in the course of disease, the virus was active and replicating. Simultaneous with that, getting to the mid-'90s, was the advent of the use [of combination therapies] first in clinical trials, and then as standard of care in the mid-'90s, '96 or so, together with the ability to measure virus in a very precise, accurate and highly sensitive way in the blood. We realized that what we thought was not active virus is, because now you look and you see a lot of virus in the blood…. we had a whole new look and approach at the extraordinary, complicated and dynamic nature of viral turnover and lymphocyte turnover.

… [Some people felt very optimistic about the possibility of eradicating the virus.] Did you feel that optimism yourself?

No. I take things with cautious optimism. I'm an optimist in that it drives you to keep going, but because of what we knew about the lymphoid tissue and because we were exploring the nature of the reservoir, I had a considerable degree of skepticism then -- and now it's been proven to be correct -- about our ability to truly eradicate the virus, because even in patients in whom you could not detect levels of virus in the plasma, when we looked in the lymphoid tissue, the reservoir was still there. It was there years after the initiation of what we felt to be effective therapy.

Then proof of the pudding was a very depressing experiment we did sometime after the mid-'90s in which we empirically discontinued drugs in individuals who were otherwise felt to be under absolutely pristine control with their antivirals. In essentially every one of the individuals, the virus rebounded right back to where it was in the beginning. That was saying that you could suppress it, but you couldn't eradicate it.

... Can you tell the story of the search for a vaccine? What were the starting assumptions?

There was an incorrect assumption that to get a vaccine would be just like getting a vaccine for any other microbe, which led to the somewhat ill-fated statement by Secretary [of Health and Human Services Margaret] Heckler back in the mid-'80s that now that we have the virus [isolated], the vaccine is a couple of years away. I think what one did not appreciate was how unique this virus is; that of all the microbes we know of, this is the only one in which the body has proven itself completely incapable of eliminating the virus from the body once it gets infected. Even with the deadliest of diseases -- the viruses of smallpox, of polio, of measles -- you get infected, there's a certain mortality; then you clear the infection, the body gets an immune response, and it's unlikely you're going to get infected again. When you develop a vaccine, you look at the body and you say, "This is what the body did to protect itself, and we're going to develop a vaccine that mimics what the body has done."

With HIV, the body has not been successful, so you don't have a framework to look and say, "Ah, this is what we want to do." The body does not develop broadly reacting neutralizing antibodies against the common isolates. The virus seems to always be a step ahead. …

A neutralizing antibody is a protein that is made by certain types of cells, that has the ability to recognize, in a very precise manner, a microbe or a virus. It binds to that and either directly clears it, or with the help of other cells clears it. We call it neutralizing for the simple reason that it neutralizes the infection. It is the standard of what a vaccine should do to prevent infection.

Then there's cell-mediated response, which is not this floating antibody in the blood, but is a cell that has the capability of recognizing an infected cell. But the cell has to be infected. The cell-mediated immunity doesn't eliminate free-floating virus; it only eliminates a viral-infected cell. That's the good news. The bad news is that the person has to already be infected for that to really have a major effect. It can be important in preventing infection, but it's most relevant in containing an infection that has already occurred.

Historically and appropriately, people started looking at antibodies as the end point of a vaccine. The only trouble is that the field was looking at the wrong antibodies, because what we didn't know at the time that we know now is that the induction naturally of neutralizing antibodies against the vulnerable components of the virus is a very difficult thing for the body to do, because those areas [on the virus] that induce the antibody don't expose themselves very regularly. So even on a natural situation, although you can induce good neutralizing antibody, it is not antibody that is able to neutralize a broad array of strains the way a neutralizing antibody against a number of other viruses is able to do. … It became very clear as the years went by that you … almost certainly need neutralizing antibody, but it's going to be a very difficult scientific task to readily induce these relevant neutralizing antibodies with a vaccine. …

As a researcher, what has the quest for a vaccine been like for you?

Yeah, it's often referred to as the holy grail of the whole AIDS research endeavor, the last final thing from a scientific standpoint that we need to accomplish before we really have come full circle. I mean, obviously … you always need a pipeline of better drugs and newer drugs. But with vaccine we've really been stymied, and that his due to the very special nature of this virus. It is really unprecedented in what it can do, how it inserts itself into the genome of the cell, the rapidity with which it can multiply or replicate, how it can change, how when it gets into a particular cell it stays there essentially for an indefinite period of time, what we call the latency of the virus so that even when you suppress the virus with antiviral drugs, when you stop the antiviral drugs, invariably the virus bounces back and starts destroying the body's immune system as it did before you treated them. With a vaccine to try and prevent an infection, the very illusive nature of this virus makes it very problematic.

I can probably describe it in simple terms by saying of all of the successful vaccines that we've made over the years against a number of microbes, including potentially lethal ones like smallpox and measles and polio and all the other viruses and vaccines that we have dealt with in the past, you generally take a look at what the particular virus or microbe in question can do to the body. And even something like smallpox in which 15 to 20 to more percent of the people die from it, the vast majority of them actually recover from smallpox. And when they recover, their body develops an immune response that you can mimic or copy so that when you come in with a vaccine, you say, "I know what a protective immune response is and I am going to aim my vaccine to create that protective immune response that people who actually got infected get." The same thing with polio -- 90-plus percent of the people who get polio do fine. Same with a variety of other infections. The people just do very, very well. So the body is telling you that if you give me the right stimulus I am going to make a response that is going to protect me.

Unfortunately, amazingly so, … of the 60 million-plus people who have been infected, of which already 23-plus percent million have died, of all of those cases, there isn't a single documented instance of once a person has established infection of the body's immune system completely getting rid of the virus. Some people do very well. They are long-term non-progressors and their immune system keeps the virus intact for a good period of time. But in no incidence that we have been able to document that it completely clears the virus from the body, which means that uniquely among viruses this virus eludes the body's immune system to a greater or lesser degree. We are going to have to overcome that scientific obstacle if we are going to get a vaccine that actually protects you against infection, what we call sterilizing immunity. So it is not going to be easy. …

… What is your feeling on microbicides?

I think it's a very important approach, which is the reason why we are heavily supporting it in our institute. There are a lot of good things about microbicides if we can get one that works, probably the most important of which is that it empowers women to take their fate in their own hands, because particularly in developing countries in which the mores in the culture do not empower women to be able to make decisions as to whether or not they want to have sex with their husband, or whether or not if they feel that they are in danger of getting infected they could say no or demand the use of a condom, in societies like that, women can get themselves in serious difficulties, including violence against them. To be able to have a mechanism whereby they can protect themselves without their male partner knowing it would be very important, particularly in those sociological settings that take place in certain countries.

... How did research into microbicides begin and then stop for a while?

... In the initial studies, what happened is that it was a material that's topically applied to the vagina, and the trial was done in a group of sex workers, and since sex workers have sexual intercourse several times a day under certain circumstances, the material that was inserted into the vagina actually inflamed the vaginal tissue, and it made people who were using it even more susceptible to HIV, so it was a real setback for the field of topical microbicides. Now we realize that the vehicle cannot be an irritant… and it's not appropriate to test it in someone who uses it six times a day.

… What do you see as some of the missed opportunities in the United States in the early years?

It's easy to go back and say, well, we didn't do this, or we didn't do this, but at the time it wasn't so crystal clear. One of the things that had always bothered me in the beginning was the concern that if we were very proactive about how we handled the risk to the blood supply, there wouldn't be enough blood to go around. Retrospectively, that just doesn't hold any water. The arguments were, "Well, be careful, because if you shut down the blood supply, then you'll do more harm than good." Well, no one was asking anybody to shut down the blood supply, but perhaps that could have been handled a little bit more aggressively, retrospectively. ...

We did relatively well in this country because we immediately started screening, but, as you know, there were major problems in Europe. France had a whole big scandal about how they handled the blood supply. I don't know if you'd call that a missed step, but I think if you had to do it over again, you may have been a little bit more proactive in jumping on that. ... It may have been better to be much more aggressive in those very early years about targeting populations, such as the gay population, about safe sex.

But people didn't want to be targeted.

Well, history is complicated. A lot of people would blame the Congress, the Reagan administration, for not jumping out on this. But I can tell you, having been there, the gay population themselves were very reluctant to hear the safe-sex message, because they were concerned that they had just recently won their sexual liberation that they had fought so many years for, and they didn't want this disease to be used as a way to retarget them.

That's an understandable concern, but I can tell you I remember very, very clearly, before HIV was discovered to be the cause of AIDS, we had a bit of a town hall meeting in the auditorium at the NIH Clinical Center, and I got up talking about this new disease that we didn't know much about, and I made a statement to a group. There were many members of the gay constituency there who were frightened, and they came to learn about it. I said, "I don't know what's going on, but I strongly urge you in your sexual interactions to use a condom, because I think we're dealing with a sexually transmitted agent." To my surprise, there were a considerable number of people in the audience who actually got up to the microphone and hooted me down like I was trying to impose my standards of sexual conduct on them. I said: "It ha[s] nothing to do with my standards of sexual conduct. I'm an infectious-disease person, and I'm telling you I think you should use a condom." There was suspicion that I was trying indirectly to suppress the gay liberation.

Again, it's easy to say the leadership didn't take the right steps, but I don't think the constituencies were necessarily ready for that. But probably all things considered, there should have been a much more aggressive public health message than what went out back then.

How did your relationship with the gay community evolve over the years?

It was an interesting situation, because the officials in the Reagan administration allowed myself and the people in the CDC to be the voice of the government and the face of the government. Now, unfortunately for us, for me at the time, being the face of the government meant you became the target for those people who justifiably felt that not enough was being done for them. For a couple of years there, it became clear that as much as I went out and tried to outreach, I nonetheless was associated with the federal government. There were a lot of barbs and spears, metaphorically speaking, coming my way. Mostly it was directed not at the scientist that I personified but the regulatory agencies like the FDA [Food and Drug Administration] with drug trials and things like that.

What had happened is that we were taking the brunt of a lot of criticism, the FDA and myself and the CDC. ... But after a little while, I began to get beyond the rhetoric and theater of the demonstrations and the smoke bombs, to really listen to what it is that they were saying, and it became clear to me, quite quickly, that most of what they said made absolute sense, was very logical and needed to be paid attention to. But their confrontational tactics tended to put off the somewhat conservative viewpoint of scientists about not deigning to get involved with people who have a disease when scientists know best or regulators know best.

Interacting with the constituencies was probably one of the most important things that I had done in my professional career. ... There was a demonstration in the early years here at the NIH, and we had everybody on campus -- we had the Montgomery County, [Md.], police; we had the NIH police; we had the FBI; mounted police, everybody. I always remember looking out the window and seeing them demonstrating, so I asked our chief of police to go down and ask them to get five or six of their leaders to come up and talk to me about what it is that they were concerned about.

Well, that was a total shock to the constituents, because no one had ever asked them, "Were you interested in hearing what I have to say?" They were always pushing them away because of their theatrical and confrontational tactics. So I invited a group of them up to my conference room, and we spent a couple of hours talking about their concerns. Again, it just confirmed in my own mind that most of their concerns were really quite valid. Not everything -- they were off base on a few things.

That was the beginning of the constructive dialogue between me and the activists. … We came to an agreement that "I'll listen to what you have to say. If I see that there's merit in it, we'll pursue it, and if there really is no merit, I'll try and explain to you why I think there's no merit," because they were on base on more things than they were off base on. …

If there was anything about all of this that was truly productive, it was that interaction between the activist community, because it really transformed the way we did things. You were trying to develop drugs and treatment protocols for a disease for which there was no treatment. At the same time that you had to do good science to get it right, you had to be sensitive to the fact that these people had nothing else and no other option. In a pristine world, you do the science first, and then you worry about everything else. You couldn't do that. That's how we came about with expanded access to drugs, how we came about with accelerating greatly the approval process and how we came about what was known as the parallel track.

A lot of people give me credit for coming [up with] the parallel track. It really wasn't me. It was the activists who said, "Why don't we try this?" And I said, "You know, that sounds like a great idea. I think I'm going to stick my neck out on this one and push it for you." ... There was a lot of concern on the part of the FDA that this would interfere with the integrity of the clinical trial process, so I took a deep breath and went out to San Francisco and said, "I'm not going to check this with anybody back in Washington." I got up and I said, "I'm absolutely in favor of a clinical trial process under the parallel track." It was one of those instances of it's easier to beg forgiveness than to ask for permission. And I did it. There was a bit of a stir in Washington for a few days to a week after, but then everyone saw the potential advantage of doing it this way. The parallel track concept became accepted, and I think that went a long way to getting access to drugs for people who needed it at the same time as we had the integrity of the scientific process….

... Was there a sense in the 1990s that you were getting AIDS under control, that instead of everyone dying immediately, it was an outpatient disease?

People were feeling, inappropriately, "Well, gee, this isn't necessarily all that bad." Then what we saw was that rebound of infection and risk-taking in some of the populations because they assumed that this isn't so bad. But when you look at the numbers, the numbers are still bad in this country. The numbers are horrendous in developing nations, but even in this country we kind of got lulled into an acceptance of this as just part of the way things are. And because of the accelerated number of new infections and people dying with HIV has reached a peak, come down and now kind of plateaued, it is not nearly on the radar screens of people the way it was back in the mid- to late '80s and maybe early '90s.

But if you look at the numbers, they're still startling: almost a million diagnoses of AIDS in this country, 900,000-plus; over half a million deaths; close to a million people who are infected. And the number that still is quite disturbing is that the so-called plateau [is] at 40,000 new infections per year. Sure, it's a plateau; it's been that way for the last more than 12 years. But it's an unacceptably high plateau, and that really reflects the combination of complacency and some shifting demographics. You have the infection now being much more prevalent in inner-city, minority young women. It's gone from less than a percent of new infections in women to now over 20 percent. ...

[How has government funding of HIV/AIDS research changed over the last 25 years?]

Well it was very clear that the first thing that the current administration did -- in the first year, not necessarily in subsequent years -- but [was to] give a big bonus in [funding] to HIV/AIDS research and I think that was because it was an important and right thing to do. …

I think it's somewhat artificial to make comparisons that are real substantive comparisons between one administration and another because if you look at the growth of the AIDS budget from the very beginning, obviously there was concern that in the early years the Reagan administration didn't pay enough attention to it. But as we got into the end of the Reagan administration, the beginning of Bush 41, it became more and more attention to it, more and more resources. Then with Clinton again more and more resources and now in the current administration there are considerable numbers of resources. So it really transcended changes in administration from the standpoint of real concrete support and approach. It was good both Democratic, Republican, bipartisan in the Congress. …

For research?

For research as well as for issues that related to how you approach the whole scene of HIV in this country. Certainly when the Clinton administration came in they were much more open about, "We need to do this," and "We'll embrace this," or not. … The Clinton administration was very readily and easily interacting with the constituency groups. Despite the fact that other administrations, the Bush administration before, didn't as readily interact, there was still a lot of good things going on behind the scenes. …

[Many people feel let down by President Clinton's position on needle-exchange programs.]

You'll always find people who are let down. Certainly the support for research in HIV/AIDS was good in the Clinton administration, good in the Bush administrations. It just was. If you look at how HIV/AIDS did, as someone who was very much focused in the research arena my viewpoint was it was really almost seamless from one administration to another.

Certainly there was great optimism as the Clinton administration came in that now the constituency groups were going to get everything that they wanted. But the cold reality is that even if you're an administration in power … you've got to deal with different ideologies, particularly in the Congress as well as even in your own administration that don't want you to go for one way or the other.

So I think that the expectations of people that now because this was a more liberal administration than the previous administration, that a lot of things were going to happen that many of the constituency groups felt were going to be automatic and then I think what they were faced with that even though you have an administration that would ideologically feel a certain way and agree with you, it isn't all that easy, sometimes, to get it done. …

And I think a very good example of that was the whole issue of needle exchange. I mean that was, it concretized what the realities of getting something through in Washington are regardless of what the philosophical approach of the administration is. … There were elements not only in the administration but strong Congressional elements who felt that despite the data which showed that needle exchange would not be an inducement for illicit drug use and would, in fact, cut down on the transmission of HIV, you would have thought that it would have been a slam dunk with the Clinton administration and those data that we would then have government support of needle exchange.

But there were a lot of elements in the government who felt that that was not the way to go; that that would be giving up on certain groups of people by allowing clean needles to be exchanged. So that was a big dose of cold water on some of the people who felt well you just take a look at the information and the right thing is going to get done, or the thing that you think is the right thing is going to get done. And the cold realities of Washington is that that's not always the case.

[What was your position on needle exchange?]

I was part of the small team that analyzed the data and recommended that we should support needle exchange. And my recommendation, and my colleagues -- it wasn't just me it was a group of about seven of us who reported to Secretary [of Health and Human Services Donna] Shalala and said that the data indicate that this is something that is not going to hurt and very likely to help. So we all thought, well that's it, it was going to happen, and it didn't happen. …

… One of the points you were making earlier was that it's important not to just think that a Western model of treatment needs to be translated to Africa. When you went to Africa, you went up into the bush on motorcycles. Tell that story.

Well, assumptions are made, sometimes decisions are made in good faith that are not well informed like a decision that either you can't do something in Africa because the facilities are not there, the infrastructure is not there, the people will not be able to comply with the therapy, or you go to the opposite extreme and you say, "Oh, sure, we will do it, but we will do it exactly the way we do it at Harvard, Yale, San Francisco, exactly the way we do it around the Washington Beltway or in downtown New York," or what have you. Both of those extremes are self defeating. One you never get off the ground and the other you're trying to do something that's unrealistic.

So we worked carefully and our model was a model that was developed by Africans. We called it the network approach, where you have a central medical center -- most countries have … one in the entire country and then they have secondary and tertiary clinics and sub-clinics with people of less medical skill but nonetheless quite devoted and that's how they get out and get into vaccinations and malaria treatments and things like that.

So we went down there and we saw that in action. We said, you know, a therapy prevention care for HIV can really work under these circumstances if you do it the African way. And I think that was a very important decision. Don't parachute in your own preconceived notion about how things can be done. Do it the way the Africans feel that they can do it.

And then when we went back on a subsequent trip, again with Secretary [of Health and Human Services Tommy] Thompson and myself and Julie Gerberding from the CDC and a whole bunch of people. The secretary brought a lot of people down to show them how this thing worked. We actually walked through it. We did a walk-through, as it were, and it was an extraordinary experience particularly for people who have never been to Africa. We had done that several times in the past, but for those who had never been to Africa to see it, we landed in Kampala, Uganda. We got into some jeeps, and we went out into the bush for a four-hour trip. Then from there we got with motorcycles and went into villages, where it was something out of a movie picture. I mean, you're in a village in the middle of nowhere [with] the health providers and the people who are the volunteers for organizations like TASO, which is very famous in Uganda, The AIDS Service Organization. We went with that group, and we saw them on the motorcycles with their bags of drugs sitting down talking to a woman in the middle of a village. ...

Those who might be prejudiced [and] are not appreciative of what goes on there will say, "Well, how could that person ever tolerate or even get involved in a regimen that requires multiple drugs every day?" You sit down and talk to her. She knew exactly what was going on. It brought us all to tears. It was amazing. She knew that she had a virus and what the virus did. The virus had already killed her husband and two of her children. She knew that she needed therapy. She knew what the virus did to the body, and she knew how important it was to regularly take her medication. But when you go in and you look in the village, and you see how the individual villages have been shattered by this disease, by this virus, and then you see people like these men and women who we went along with, the TASO group, to deliver the medicines to them, you saw that this woman who she said several months before she was just skin and bones, she was now back up taking care of the remainder of her children, being the leader of her household, I mean, it was all there, the whole transforming event right there.

At least the people who saw it realized that in situations where you do it with our resources and the African way of doing it, it will work. That's why the president's program is working, and that's why the Global Fund will work.

… Why is there the need to do PEPFAR when there is already the Global Fund?

Good question that sometimes gets misinterpreted. The Global Fund is doing fine now. It has got a good leader, Richard Feachem. It has got a lot of countries getting involved. Please don't forget that the United States is the major contributor to the Global Fund in addition to [PEPFAR].

But the White House felt that if they were going to be able to get a commitment of $15 billion from the American public through the Congress at a time when it was clear that resources were being constricted, they wanted to have something for which they were accountable so that they had the money, they would give it to a particular NGO [non-governmental organization] and say, "You get the money if you show that you are accountable to spending it properly, and if not, we're going to pull the money back." It had a lot to do with the accountability.

Now, that doesn't mean or imply that the Global Fund will not have accountability. But if you give it to the Global Fund, once you give it to the Global Fund, you don't have any accountability for it because it is now out of your hands. …

Now, a lot of people wanted to say, "Why don't you throw all $15 billion into the Global Fund?" That was a judgment call, and I think you have to be fair to both sides. The decision was they wanted more of a degree of accountability than they could get if they went with the Global Fund, because remember, at the time of the Global Fund, no money had been disbursed at all, and there was a lot of preparing in central headquarters, and not very much came out. Now, I don't mean that to be a criticism of the Global Fund, because the Global Fund is really starting to move now. But at the time the decision was made, we wanted more accountability to us, and that's the reason why they did it bilaterally.

What is the influence of the Christian right and the evangelical movement on PEPFAR?

It's absolutely exaggerated. There's no doubt about that, because it is very clear -- because I wrote it into the program -- that part of the program is going to be based on the Ugandan model that works, which includes condoms. It's ABC: abstinence for those who can delay sexual debut; [being faithful] for individuals who are in a monogamous relationship; and if you are not, then condoms are what we should be doing. Somehow or another that got misconstrued. I've heard people say, "Oh, one-third of all the money is going for abstinence." That's absolutely nonsense. Twenty percent of the money is going to go into prevention. Of that, a third would go into those programs. Not everyone agrees with what people's different philosophical bents are about prevention, but this is a program that is comprehensive, and it includes condoms.

... One could say there was a bizarre confluence of political figures coming together around this issue -- Bono, [lead singer of the Irish band U2] President Bush. What was going on? Why did all these political forces come into play?

This was an example of the enormity of the problem and the need for bold action that puts aside partisanship, that puts aside ideology, even though there were these criticisms that too much ideology got involved. But take a look at what's happened. It was a nonpartisan realization that we're in a public health crisis in the world, and as a rich country, we have the opportunity to have an enormous impact. It's for that reason that the president, who felt that strongly, didn't turn to a politician, didn't turn to an ideologue. He turned to people like me and my colleagues who are well known as being totally nonpartisan public health people who only care about public health. He said, "Make the plan." During the writing of the plan, there were no ideologues looking over my shoulder saying, "Oh, you've got to do this; you've got to do that." He said, "Do what you think is the best." And it got bipartisan support in the Congress. It got support from people in the administration, outside of the administration.

I remember a conversation late into the middle of the night in my home with Bono as we were eating pasta that I cooked for him in my back porch talking about what the best way to go about this thing is. You have a rock star talking to me who is helping to put together something for the president, and we're getting bipartisan support, which is sometimes unusual in this city. We are clearly getting bipartisan support for this. It was really a wonderful thing that happened.

…Is it right to characterize this as your life's work?

Oh, totally. Totally. This is what consumes me.

Are you satisfied with your choice of focusing on this? What's the value of doing it?

Well, this is one of the greatest public health challenges that the world has ever faced. It is an opportunity, a challenge and a great stress to be in the middle of it as I have been for the last 24 years, 25 years. I wouldn't have had it any other way. This is something that is so important. My training is in infectious diseases and immunology. This is a virus that destroys the body's immune system. It was almost as if when I went into medical school and did my postdoctoral training that I was training for the AIDS epidemic before it even happened. My being involved with it has been my passion and my life's work for now two and a half decades.

Do you ever get the feeling, when you go to developing countries and see the kind of horror of the disease that we once saw here in the West, that you're reliving your youth, when you first saw the disease?

Oh, yeah. There are memories that are embedded in me. I used to treat diseases before HIV, some of which we have fortunately developed cures for, where everybody would walk out of the hospital healthy. When the AIDS epidemic hit and we first started admitting patients in 1981, nobody left the hospital. They essentially all died. That was a tremendous cultural shock for a physician like myself and my colleagues to see almost everybody die. If they don't die on this admission, they'll go out and come back, and they die in the next admission. It was really terrible.

That is totally magnified when you go to a sub-Saharan African country, because not only is the situation in the hospitals in the sub-Saharan African countries similar to the way the things were in the hospital when we first started taking care of patients, the mortality was so strikingly high, but the spillover into society is so obvious when you are in a country like Botswana, South Africa, Uganda, Kenya and places like that, where a measurable, significant proportion of the population is infected, and when you walk around, there isn't a village or a home or a community that hasn't been severely impacted by HIV. It is kind of like back in the '80s when you went to the Castro district of San Francisco or the Village in New York City; it was palpable how the community had been so disrupted and wrecked by this terrible disease. You go to sub-Saharan Africa, it's like everything is a Castro district, everything is a Greenwich Village when you look at the proportion of the people that are infected. That is quite compelling and depressing.